NM_001001331.4:c.3357G>A

Variant names:

• chr3-10338239-C-T
• rs35678
• NM_001001331.4:c.3357G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001001331.4(ATP2B2):​c.3357G>A​(p.Ala1119Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 1,613,952 control chromosomes in the GnomAD database, including 166,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17883 hom., cov: 33)
  • Exomes 𝑓: 0.44 (148137 hom.)
• Consequence: ATP2B2 NM_001001331.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.53
• Publications: 25 publications found

Genes affected

ATP2B2 (HGNC:815): (ATPase plasma membrane Ca2+ transporting 2) The protein encoded by this gene belongs to the family of P-type primary ion transport ATPases characterized by the formation of an aspartyl phosphate intermediate during the reaction cycle. These enzymes remove bivalent calcium ions from eukaryotic cells against very large concentration gradients and play a critical role in intracellular calcium homeostasis. The mammalian plasma membrane calcium ATPase isoforms are encoded by at least four separate genes and the diversity of these enzymes is further increased by alternative splicing of transcripts. The expression of different isoforms and splice variants is regulated in a developmental, tissue- and cell type-specific manner, suggesting that these pumps are functionally adapted to the physiological needs of particular cells and tissues. This gene encodes the plasma membrane calcium ATPase isoform 2. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ATP2B2 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal dominant 82

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.3600707E-5).
• BP6: Variant 3-10338239-C-T is Benign according to our data. Variant chr3-10338239-C-T is described in ClinVar as Benign. ClinVar VariationId is 1273978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001331.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B2	NM_001001331.4	MANE Select	c.3357G>A	p.Ala1119Ala	synonymous	Exon 22 of 23	NP_001001331.1	Q01814-1
	ATP2B2	NM_001438646.1		c.3264G>A	p.Ala1088Ala	synonymous	Exon 20 of 21	NP_001425575.1
	ATP2B2	NM_001353564.1		c.3222G>A	p.Ala1074Ala	synonymous	Exon 20 of 21	NP_001340493.1	Q01814-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B2	ENST00000360273.7	TSL:5 MANE Select	c.3357G>A	p.Ala1119Ala	synonymous	Exon 22 of 23	ENSP00000353414.2	Q01814-1
	ATP2B2	ENST00000452124.2	TSL:1	c.3264G>A	p.Ala1088Ala	synonymous	Exon 19 of 20	ENSP00000414854.2	Q01814-8
	ATP2B2	ENST00000397077.6	TSL:1	c.3222G>A	p.Ala1074Ala	synonymous	Exon 19 of 20	ENSP00000380267.1	Q01814-6

Frequencies

GnomAD3 genomes AF: 0.477 AC: 72478 AN: 151986 Hom.: 17869 Cov.: 33

Gnomad AFR AF: 0.547

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.463

GnomAD2 exomes AF: 0.491 AC: 123399 AN: 251364 AF XY: 0.488

Gnomad AFR exome AF: 0.557

Gnomad AMR exome AF: 0.689

Gnomad ASJ exome AF: 0.389

Gnomad EAS exome AF: 0.547

Gnomad FIN exome AF: 0.394

Gnomad NFE exome AF: 0.407

Gnomad OTH exome AF: 0.452

GnomAD4 exome AF: 0.443 AC: 648055 AN: 1461850 Hom.: 148137 Cov.: 69 AF XY: 0.447 AC XY: 325286 AN XY: 727226

African (AFR) AF: 0.552 AC: 18482 AN: 33480

American (AMR) AF: 0.677 AC: 30256 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 10048 AN: 26136

East Asian (EAS) AF: 0.594 AC: 23591 AN: 39698

South Asian (SAS) AF: 0.619 AC: 53400 AN: 86258

European-Finnish (FIN) AF: 0.402 AC: 21449 AN: 53386

Middle Eastern (MID) AF: 0.482 AC: 2779 AN: 5768

European-Non Finnish (NFE) AF: 0.415 AC: 461204 AN: 1112004

Other (OTH) AF: 0.445 AC: 26846 AN: 60396

GnomAD4 genome AF: 0.477 AC: 72536 AN: 152102 Hom.: 17883 Cov.: 33 AF XY: 0.482 AC XY: 35852 AN XY: 74340

African (AFR) AF: 0.547 AC: 22715 AN: 41490

American (AMR) AF: 0.581 AC: 8896 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1335 AN: 3472

East Asian (EAS) AF: 0.554 AC: 2854 AN: 5150

South Asian (SAS) AF: 0.619 AC: 2987 AN: 4822

European-Finnish (FIN) AF: 0.390 AC: 4136 AN: 10602

Middle Eastern (MID) AF: 0.503 AC: 147 AN: 292

European-Non Finnish (NFE) AF: 0.413 AC: 28068 AN: 67956

Other (OTH) AF: 0.460 AC: 970 AN: 2110

Alfa AF: 0.439 Hom.: 9493

Bravo AF: 0.493

TwinsUK AF: 0.415 AC: 1538

ALSPAC AF: 0.424 AC: 1635

ESP6500AA AF: 0.537 AC: 2365

ESP6500EA AF: 0.415 AC: 3570

ExAC AF: 0.486 AC: 59068

Asia WGS AF: 0.578 AC: 2012 AN: 3478

EpiCase AF: 0.417

EpiControl AF: 0.408

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.035
DANN	Benign	0.94
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.000034	T
PhyloP100		-3.5
GERP RS		-9.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35678; hg19: chr3-10379923; COSMIC: COSV59497074;